There is considerable evidence that prostaglandins (PGs), products of the cyclooxygenase pathway of arachidonic acid (AA) metabolism, contribute to the hyperalgesia associated with tissue injury and inflammation. However, poor correlation between the concentration of prostaglandin and symptom intensity, as well as the inability of inhibitors of the cyclooxygenase pathway to consistently produce analgesia, suggested that other mediators of inflammation were involved in clinical conditions associated with hyperalgesia. We have, in fact, characterized the hyperalgesic effects of leukotrienes (LTs), a newly discovered class of AA metabolites whose synthesis is not blocked by cyclooxygenase inhibitors. We showed that leukotriene B4 (LTB4), a product of the 5-lipoxygenase pathway of AA metabolism, reduced nociceptive thresholds and sensitized single nociceptor at low intracutaneous doses. The hyperalgesia induced by LTB4 was also distinguished from PG-induced hyperalgesia by its dependence on the polymorphonuclear leukocyte (PMNL). We have tentatively identified a hyperalgesic factor derived from LTB4-stimulated PMNLs as (8R,15S)-diHETE, a product of the 15-lipoxygenase pathway. In addition, we have detected hyperalgesic activity, present at physiological doses, for two other LTs. We propose to survey the hyperalgesic properties of these and other LTs, to establish the specific neuronal and non- neuronal cells upon which LTs act to produce hyperalgesia, and to establish the contribution of LTs in animal models of hyperalgesia. We have, in addition, recently developed an animal model, using cutaneous application of chloroform, of noradrenaline (NA)- sensitive hyperalgesia, such as occurs clinically in reflex sympathetic dystrophy and causalgia. We propose to further characterize NA-sensitive hyperalgesia and also to study the effect in this model of endogenous substances that are active on the sympathetic postganglionic neuron.